DR ANDREAS E.

ALBERS (Orcid ID : 0000-0001-5614-9873)

Article type : Original Manuscript

Accepted Article
Saddle nose deformity and septal perforation in
granulomatosis with polyangiitis

Running title: Saddle nose deformity and septal perforation in GPA

Annekatrin Coordes1, Sonja Maike Loose1, Veit M. Hofmann1, Grant S. Hamilton III

MD4, Frank Riedel2, Dirk Jan Menger3, Andreas E. Albers1*

1 Department of Otorhinolaryngology, Head and Neck Surgery, Charité –

Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-

Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin,

Hindenburgdamm 30, 12200 Berlin, Germany.

2 Center of Otorhinolaryngology Rhein-Neckar, Stresemannstr. 22, 68165

Mannheim, Germany

3 Department of ENT-FPS, University Medical Center Utrecht, The Netherlands

4 Department of Otorhinolaryngology, Mayo Clinic, 200 First St. SW., Rochester, MN, USA
55905

*Corresponding author: Andreas E. Albers, MD, PhD, Department of

Otorhinolaryngology, Head and Neck Surgery, Charité – Universitätsmedizin Berlin,

Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail:

andreas.albers@charite.de; Phone: (+49) 30 – 450 555 602; Fax: (+49) 30 - 450 555

970

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/coa.12977
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 "Compliance with Ethical Standards"

Funding: No funding was received for this study.

Conflict of Interest: The authors have no conflict of interest to declare.
Ethical approval: This article does not contain any studies with human participants
Accepted Article
performed by any of the authors.

Key words: Nasal reconstruction, graft, autologous, allogeneic, granulomatosis with

polyangiitis, M. Wegener

Abstract:

Background: Patients who have granulomatosis with polyangiitis (GPA, syn. M.

Wegener) often develop an external nose deformity which may have devastating
psychological effects. Therefore, reconstruction of nasal deformities by rhinoplasty
may become necessary to achieve a normal appearance.

Objective of review: The aim of this systematic review was to investigate the efficacy
and safety of surgical reconstruction in external nasal deformities and septal
perforation in GPA patients.

Search strategy: A systematic literature search with defined search terms was
performed for scientific articles archived in the MEDLINE-Database up to June 10th,
2016 (PubMed Advanced MEDLINE Search), describing management of cases or
case series in GPA patients with saddle nose deformity and/or septal perforation.

Results: Eleven of 614 publications met the criteria for this analysis including 41
GPA patients undergoing external nasal reconstruction and/ or septal reconstruction
with a median follow-up of 2.6 years. Overall, saddle nose reconstruction in GPA
patients is safe even if an increased rate of revision surgery has to be expected
compared with individuals without GPA undergoing septorhinoplasty. Most implanted
grafts were autografts of calvarial bone or costal cartilage. For septal perforation
reconstruction, few studies were available. Therefore, based upon the available data
for surgical outcomes, it is impossible to make evidence-based recommendations .
All included GPA patients had minimal or no local disease at the time of
reconstructive surgery. Therefore, the relationship between disease activity and its
impact on surgical outcomes remains unanswered. The potential impact of immune-

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 modulating medications on increased complication rates and the impact of
prophylactic antibiotics are unknown.

Conclusions: This study systematically reviews the efficacy and safety of surgical
Accepted Article
reconstruction of external nasal deformities in GPA patients for the first time. Saddle
nose reconstruction in GPA patients with minimal or no local disease is a safe
procedure despite an increased rate of revision surgery. Further research is required
regarding the impact of antibiotic prophylaxis, immune-modulating therapy, long-term
outcomes, and functional outcomes measured with subjective and objective
parameters.

Keywords: saddle nose, septal perforation, reconstruction, granulomatosis with

polyangiitis, Wegener's granulomatosis

Introduction:
Granulomatosis with polyangiitis (GPA), previously known as Wegener's
granulomatosis, is a systemic vasculitic disease characterized by necrotizing
granulomas and vasculitis of small and medium-sized vessels (1). The disorder was
first described by Klinger in 1931 (2) and by Wegener in 1939 (3). Klinger et al.
published the first description of a case of GPA, but called it atypical Polyarteriitis
nodosa, while Wegener described his cases as a separate granulomatous disease.
The mean age at initial diagnosis is 55 years. In Europe, an annual incidence of
10/1.000.000 has been reported (4, 5). The disorder classically involves the upper
airways, lungs and kidneys. The diagnosis is made through a combination of
physical examination, laboratory studies and tissue biopsy (6). The currently used
classification criteria for GPA diagnosis are based on a consensus paper (9).
Serologic testing includes the determination of antineutrophil cytoplasmatic
antibodies (cANCA) and proteinase 3 antibodies (anti-PR3). Staphylococcus aureus
superantigens are suspected to be involved in the production of PR3-ANCA (7).
Bacterial superinfection with Staphylococcus aureus has been recognized as a
potential risk factor for disease relapse (8).

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 Involvement of the head and neck region occurs in 80-95% of cases and may be the
first symptom of GPA. In 60-90%, manifestations are located in the nasal cavity and
paranasal sinuses, also indicating the degree of disease activity (10). Over 25% of
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GPA patients have only nasal symptoms (11). Patients with active sinonasal disease
present with nasal crusting (69%), chronic rhinosinusitis symptoms (61%), nasal
obstruction (58%), and nasal discharge (52%) (12). Further complaints include foul-
smelling rhinorrhea, recurrent epistaxis, hyposmia, anosmia, and epiphora caused
by an obstruction of the lacrimal system. The primary therapy for systemic disorders
is systemic immuno-suppressive medication, however, non-cosmetic, functional
sinonasal procedures are required in medically refractory head and neck
manifestations (e.g. endoscopic sinus surgery for chronic rhinosinusitis or mucocele
decompression, surgery of the lacrimal duct for chronic epiphora, and orbital
decompression for pseudotumor) (12).
The anterior part of the nasal septum is one of the most frequently involved areas in
GPA (13). With disease progression mucosal erosions and formation of scars may
become visible (14). The cartilaginous structures of the outer nose and septum are
generally more severely involved than the bony nasal dorsum and septum. Extended
disease may cause progressive loss of septal support leading to enlarged anterior
septal perforations (15) which occur in 33% of cases (12) resulting in significant
collapse of the cartilaginous nose. Deformities range from loss of dorsal height to a
shortened nasal length with tip deprojection and retraction of the nasolabial angle.
Bluish discoloration of the skin may occur concurrently with a developing saddle
nose deformity. The loss of tip support results in a shortened nose with the
characteristic saddle nose deformity, which is present in 23% of GPA patients (12).
The psychological impact on these chronically ill patients with saddle-nose deformity
is particularly high. Some patients are so self-conscious that they limit their social
interactions and suffer from a significantly diminished quality of life. Additionally, the
loss of the nasal framework also worsens the nasal obstruction and increases
anosmia. For these reasons, these GPA patients ask for surgical reconstruction.
So far, the general consensus has been that surgical procedures on the nose should
be avoided in GPA patients (13, 16, 17). The restraint in surgical intervention is
based on concerns that an attempt to repair the nose with tissue damage and
induction of wound healing caused by the surgery may result in a flare-up of the GPA
symptoms both locally and systemically. According to this line of reasoning,
arguments include a fear of higher complication rates possibly caused by a reduced

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 tissue perfusion with consecutive poor wound healing, increased reconstructive graft
resorption. These effects may be increased by the intake of immunosuppressive
medications with adverse effects on wound healing. Since the prevalence of most
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systemic diseases is very rare, recommendations are based on the analysis of single
case reports and case series with a limited number of patients only. Consequently,
many patients are counselled that “nothing can be done” which is often devastating
news and delays reconstruction. This delay in treatment can lead to further
contraction of the skin and mucosal nasal lining–resulting in an even more
challenging surgical problem.

This is the first study to systematically review the available data with regard to
efficacy and safety of surgical reconstruction of external nasal deformities in this
unique patient group.

Materials and methods

Literature search strategy

A systematic literature search was performed for scientific articles on MEDLINE

(PubMed Advanced MEDLINE Search) describing cases or case series of patients
with saddle nose deformity and septal perforation in GPA. The time period for the
study included all articles published up to June 10th, 2016.

The search was performed using the following "MeSH" terms for GPA: ´Wegener's
granulomatosis`, ´granulomatosis` AND ´polyangiitis`, ´granulomatosis with
polyangiitis`, ´wegeners` AND ´granulomatosis`.

To investigate the extent of nasal impairment and septal perforation in Wegener's

granulomatosis we used the following combination of search terms:

(´granulomatosis with polyangiitis`[MeSH Terms] OR (´granulomatosis`[All Fields]

AND ´polyangiitis`[All Fields]) OR ´granulomatosis with polyangiitis`[All Fields] OR
(´wegeners`[All Fields] AND ´granulomatosis`[All Fields]) OR ´wegeners
granulomatosis`[All Fields]) AND (´nose`[MeSH Terms] OR ´nose`[All Fields])

and

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 (´granulomatosis with polyangiitis`[MeSH Terms] OR (´granulomatosis`[All Fields]
AND ´polyangiitis`[All Fields]) OR ´granulomatosis with polyangiitis`[All Fields] OR
(´wegeners`[All Fields] AND ´granulomatosis`[All Fields]) OR ´wegeners
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granulomatosis`[All Fields]) AND ´septal`[All Fields] AND ´perforation`[All Fields]

and

(´nasal septal perforation`[MeSH Terms] OR (´nasal`[All Fields] AND ´septal`[All

Fields] AND ´perforation`[All Fields]) OR ´nasal septal perforation`[All Fields]) AND
´systemic`[All Fields] AND (´disease`[MeSH Terms] OR ´disease`[All Fields]).

Additionally, we checked references cited in original or review articles which were

not retrieved by the initial literature search.

The included studies evaluated the surgical treatment of nasal defects like the
saddle nose deformity and septal perforation in GPA. Included articles were
published in German, English and French. We excluded studies investigating
systemic diseases without any reference to GPA or extranasal manifestations in
GPA patients. Finally, we also marked studies with conflicts of interest (e.g.
manufacturers’ interests).

Data extraction

From all eligible studies, the relevant data was extracted by two of the authors (A.C.
and S.M.L.) independently. Discrepancies were discussed by both co-authors. All
relevant information was described and presented such as author information, date
of publication, time frame of the study, country, demographic characteristics of the
patients (age and sex), surgical management, and outcomes.

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 Results

Description of the included studies

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A total of 11 out of 614 publications met the criteria for this analysis presented in
Figure 1 (14, 18-27) and described the efficacy and safety of surgical reconstruction
of external nose deformities and/or septal perforations in GPA patients. The main
characteristics of the studies are presented in Table 1. Studies were published
between 1990 and 2014. The total number of included GPA patients undergoing
external nose reconstruction and/or nasal septum reconstruction was 41. The
presented cases include 33 female and 3 male patients while two studies did not
describe the gender.

Saddle-nose deformity

Saddle-nose deformity was treated surgically in all included studies to improve both
functional and aesthetic outcomes. Surgical interventions were exclusively
performed in a state of remission. In all cases, grafts and/or flaps were used to
augment the structural cartilaginous and mucosal defects respectively, and the
temporary dermal filler Restylane® in one case.

Noguchi et al. (18) and Duffy et al. (20) suggested in 1991 and 1998 a technique
using costal cartilage for dorsal and septal support combined with bilateral well-
vascularized musculomucosal flaps for nasal lining replacement. To reconstruct the
nose internally, Noguchi et al. performed a transverse incision in the nasal dorsum
and used bilateral nasolabial flaps with the pedicles based on infraorbital vessels
(18). Duffy et al. performed bilateral lateral rhinotomy and used musculomucosal
flaps with blood supply from the facial artery (20). In both cases, a second procedure
was required to debulk the intranasal pedicles of the flaps to improve the intranasal
air passage. Both postoperative patients´ courses were uncomplicated. Additionally,
Noguchi et al. (18) planned an additional augmentation of the depressed anterior
nasal spine to improve the nasolabial angle. In the same time period in 1990, Pirsig
et al. (19) suggested a two step procedure. In a first step, the reconstruction of the
upper lateral cartilages of the nasal dorsum was performed using conchal cartilage

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 via an extranasal incision in the deepest part of a furrow along the piriform aperture.
Due to disease recurrence, further augmentation of the bony dorsum had been
postponed into the future. The auricular concha transplant remained intact without
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signs of resorption after two years despite disease recurrence.

Congdon et al. (23) published a series of 13 cases of GPA patients undergoing

reconstructive rhinosurgery. Patients who underwent septoplasty alone or repair of
the septal perforation were excluded. For reconstructions, costal cartilage (40%),
temporoparietal bone (calvarial bone graft, 27%), irradiated rib (7%), irradiated dura
(7%), autologous conchal cartilage (7%), iliac crest (7%) and bony septum (7%)
were used. In one case with an alar rim reconstruction, an auricular composite graft
was used. The overall rate of early complications was 6% (1 of 16) caused by early
wound infection. This patient deferred surgical revision. The late complication rate
was 19% (3 of 16) because of graft resorption 10 and 26 month postoperatively. Two
out of twelve patients with saddle nose deformities required one and two revision
rhinoplasties respectively, (primary success rate 77%, overall success rate 92%).
One of the revision surgeries was successful, the other failed secondary to graft
resorption 8 months after surgery. However, the second revision was successful.The
resorbed grafts were an irradiated rib (1 of 1), an irradiated dura mater (1 of 1) and a
calvarial bone (1 of 4). The success rates for the autologous transplants using
calvarial bone and costal cartilage were 75% (3 of 4) and 83% (5 of 6), respectively.
Costal cartilage was used in the patient with wound infection and calvarial bone for
the second revision case. No case with local or systemic flare-up of the GPA and no
case of accelerated disease in the postoperative period was observed. However,
disease severity influenced the surgical success rate. While patients with localized
GPA in the head and neck area displayed an overall success rate of 88% those with
systemic involvement of the lungs had a 60% likelihood of success. Anamnestically,
10 in 13 patients reported an improved nasal airway after surgery, while the three
remaining patients did not mention their postoperative airway.

Shipchandler et al. (22) reconstructed four saddle-nose deformities using a split

calvarial bone L-shaped strut via an external rhinoplasty approach. The study
included 15 patients who underwent this rhinoplasty technique (11 for other causes).
Wound infection, dislocation or resorption of the grafts did not occur during the mean
follow up of two years.

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 Nishiike et al. (21) reconstructed one saddle nose deformity using autologous iliac
crest bone. In the follow-up of three years, disease relapse caused left dacryocystitis
and the patient had to undergo endoscopic dacryocystorhinostomy, however, the
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reconstructed nose remained intact.

Vogt et al. (24) used an open rhinoplasty approach for restoration of the nasal
framework with an L-shaped rib cartilage graft. At the time of surgery, the disease
was in remission for all the patients except one with minimal local disease. The
external form and function of the reconstructed nose was preserved during the
follow-up without any signs of resorption of the rib cartilage grafts despite the
immunosuppressive medication of all four patients. The patients experienced good
aesthetic and functional results.

Sepehr et al. (25) published a series of 10 cases of GPA patients undergoing open
rhinoplasty with autologous costal cartilage grafts for reconstruction. Perioperative
antibiotics were not routinely used. Four patients suffered for postoperative
complications (40%). Two patients experienced local wound infection that was
responsive to antibiotics and two patients required revision rhinoplasty because of
graft resorption and columellar necrosis (primary success rate 80%, overall success
rate 100%). One of the patients requiring revision surgery experienced reactivation
of the disease 3 months postoperatively. Finally, the outcome was successful in both
function and form. The patients with more aggressive GPA and involvement of
multiple organ systems healed without any postoperative complications, however,
their involved physicians confirmed medically controlled disease in remission.

Qian et al. (26) performed an open rhinoplasty approach with L-shaped rib cartilage
grafts. Postoperatively one revision was performed for some minor asymmetry of the
nostrils. All patients experienced good aesthetic results. According to the local
institutional protocol. quiescent disease activity and a maximum acceptable dose of
10 mg Prednisolone daily was recommended at least six months prior to surgery.
Antibiotics were initially prescribed intravenously and then orally, in conjunction with
a topical antibiotic cream. In addition, intravenous dexamethasone was applied to
provide a steroid cover to reduce postoperative swelling and vomiting. This regimen
resulted in good outcomes and no infections. However, one patient experienced a
mild flare-up in GPA symptoms two months following the surgery which was

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 successfully controlled by the additional immunosuppressant rituximab and did not
cause any nasal instability.

Bennett et al. 2010 (27) described a case of a patient with nasal collapse secondary
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to GPA with unstable disease who had benefited from the temporary dermal filler
Restylane® (hyaluronic acid) (Galderma Laboratories, L.P., Fort Worth, TX) whilst
awaiting formal nasal reconstruction.

Septal perforation

Studies describing the treatment of nasal septum perforations without already

existing saddle nose deformities are scarce. Diamantopoulos et al. (28) investigated
patients with nasal septal perforations and found cANCA positive serology in 6 of 74
GPA patients. The clinical appearance of the septal perforation does not predict the
clinical or histological diagnosis. Often the septal perforation becomes apparent
when the diseased tissue is resorbed during disease remission (13). Perforations in
GPA patients are often very large (13, 29). Sachse et al. (14) have described the
successful surgical closure of a large nasal septum perforation in a GPA patient with
well-cared for nasal mucosa. Closure was achieved by bilateral mobilization of
inferior turbinate pedicled mucosal flaps and interposition of costal cartilage.

In the ten studies found for surgical saddle nose reconstruction, the septal
perforations were separately mentioned in case reports (18-21). Noguchi et al. (18)
and Duffy et al. (20) used well-vascularized musculomucosal flaps for nasal lining
replacement in addition to costal cartilage and concurrently performed
septorhinoplasty. The concomitant septal perforation in the case series with saddle
nose reconstruction can be assumed. However, these studies focused on the
reconstruction of the nasal dorsum and if septal closure of perforations were
performed was not mentioned (21-26).

It is unclear whether the few reports represent the lack of attempted repairs or the
absence of successful results. The prominent crust formation, colonization of
Staphylococcus. aureus and risk of relapse heighten the risk of failure (30).
Rasmussen et al. (13) concluded that the septum can be surgically treated only in
extremely rare cases with GPA due to the chronic colonization with S. aureus.
Therefore, Gubbels et al. (30) propose surgical treatment for septal perforations only

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 on patients with a small perforation with healthy mucosa at the margin. Kridel (15)
suggested the application of petroleum jelly or estrogen-containing nasal sprays
instead of surgical treatment of septal perforations in patients with mild symptoms. In
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GPA patients with persistent active disease or failed closure of a perforation,
implantation of a septal button is a possible alternative (14).

Discussion

External nasal deformity is one of the more devastating psychological effects in GPA
patients. Dorsal nasal augmentation represents a major determinant for improved
quality of life in these patients. The broad spectrum of different techniques that has
been described and discussed extensively in the literature highlights the importance
of a well-balanced and aesthetically pleasing dorsum. Consequently, rhinoplasty
may become necessary to reconstruct saddle nose deformities and nasal septal
perforations in patients with systemic diseases to restore function and to support
normal social participation. The aesthetic defects depend on the localisation and
extent of the septal defect and dorsal support. The impairment can range from loss
of dorsal height to a shortened nasal length with tip deprojection, excessive tip
rotation and retraction of the nasolabial angle (25).

Summary of main results

In general, due to the relative rarity of numerous systemic diseases including GPA,
recommendations on the treatment of nasal deformities are based on single case
reports or case series only. Furthermore, most GPA patients are treated by
nonsurgical physicians who may not be aware of possible reconstructive techniques.
Therefore, this systematic review investigated the efficacy and safety of surgical
reconstruction of external nasal deformities and/or septal perforation in GPA patients
as an effort to support clinical decisions on the basis of the currently available data.
Eleven publications met the inclusion criteria for this analysis (14, 18-27) which
included a total of 41 GPA patients undergoing external nasal reconstruction and/or
septal reconstruction. More than 90% were women. The median follow-up was 2.6
years.

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 Adequate methods for correction of dorsal defects have been discussed in numerous
publications. Optimal results in dorsal augmentation require a thorough
understanding of technique-related advantages and their distinct drawbacks. Overall,
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saddle nose reconstruction in GPA patients is safe even when compared to a typical
collection of septorhinoplasty patients, however an increased rate of revision surgery
has to be expected. The surgery greatly improves the quality of life in these patients
(23). The severity of the saddle nose deformity determined the method of
reconstruction, ranging from dorsal repair (onlay or extended spreader grafts) to two-
dimensional L-shaped strut grafts. In one case, even a filler was used.

The choice of the ideal grafting material, and the technique applied for correction of
significant dorsal nasal defects remains a matter of discussion. The variety of
implantable materials includes autologous and non-autologous grafts.

Allografts showed higher complication rates, such as infection and resorption (31,
32). However, in primary and revision cosmetic rhinoplasty, homologous cartilage
grafts, namely irradiated rib, has been shown to have low complication rates and
good long-term results (33, 34). In the included studies different autologous materials
were used for augmentation and reconstruction, ranging from osseous grafts from
the calvarium and iliac crest, as well as cartilaginous grafts from the septum, auricle,
and rib.

As stated by others previously, the ideal grafting material should be easily obtainable
with no considerable and painful surgery in the donor area, it should be well tolerated
by the tissues of the recipient area, should show no tendency to migrate through the
skin or mucous membrane surfaces. Further it should resist infection and absorption,
retain its shape and volume and should be cost-effective (35).

Depending on the amount or stability of tissue required for dorsal nasal

augmentation, autologous cartilage grafts can be obtained from the nasal septum,
the auricular concha, or the rib. Because of the extent of defects in GPA patients a
sufficient amount of cartilage often is not available from the nasal septum which itself
may already be perforated. Auricular cartilage may be of limited use because of its
intrinsic curved shape, and its increased risk of warping with ongoing scar
contracture. Reconstruction of complex nasal defects or deformities may therefore
require a considerable amount of costal cartilage for grafting.

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 In this review, we found good results in particular for calvarial bone (22, 23) and
costal cartilage (18, 20, 23-26), which were used in 8 of 40 (20%) and 26 of 40
(65%) external nasal reconstructions. Shipchandler et al. (22) reported an average
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follow-up of 20.8 months in GPA patients with calvarial bone and did not note any
complications except discrete dorsal contour irregularities. However, other studies
showed long-term resorption of calvarial bone (36, 37). In cases of significant
contour deformity and loss of structural support, costal cartilage has been
recommended as the current gold standard for reconstruction (38). In rheumatologic
diseases, such as GPA, more severe loss of cartilage is common and the defect is
often too large for septal and auricular cartilage to provide sufficient volume and
support for the reconstruction of the osseocartilaginous framework. Irradiated
homogenous grafts were exposed to a higher risk of absorbtion absorption, since
two of two irradiated grafts failed (23). In patients with unstable disease, a dermal
filler was successfully used to in one case to temporarily camouflage structural
defects (27). More data on the safety of dermal fillers in patients with vasculitis is
prudent before recommending routine use.

The study also investigated the surgical treatment of GPA patients with septal
perforation and without saddle nose deformity. We only found one case where a
costal cartilage implant and bilateral inferior turbinate flaps were used (14). For
septal perforation reconstruction, there is not enough information regarding the
outcome. Therefore, based on current knowledge surgical treatment should be
closely monitored in study-settings and results be published to increase our common
knowledge for the future benefit of patients. Pedicled flaps for mucosal
reconstruction have been described in selected cases for the reconstruction of the
septal mucosal lining in conjunction with costal cartilage during septorhinoplasty (18,
20). Another possible alternative to surgical therapy are silicone obturator buttons to
close septal perforations (23, 30). Some institutions can fabricate custom septal
prostheses (39).

The revision rate for GPA patients undergoing external nasal reconstruction appears
to be higher than in the typical septorhinoplasty population, where the published
success rate is approximately 95-100% for the primary surgery (40). The success
rates in the analysed studies varied between 77-100% for the primary reconstruction.
Four studies reported of six patients requiring revision surgery (18, 23, 25, 26). In the

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 literature, there is consensus that surgical intervention of the nose of GPA patients
may only be performed in a state of remission. The total rate of documented cases
with disease flare-up was 4 out of 40 (10%) cases (19, 21, 25, 26). One patient
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required surgical revision as the disease recurrence caused graft resorption (25), the
other three cases resolved after medical treatment (19, 21, 26).

Most studies do not describe the severity of the GPA disease. In 3 studies, 7 out of
23 (30%) patients had another organ manifestation exclusive of the upper respiratory
system (21, 23, 25). Congdon et al. (23) reported a success rate of 60% for patients
with systemic disease involvement compared with 88% for GPA patients with only
upper airway involvement. However, Sepehr et al. (25) did not find increased
postoperative complications in patients with more aggressive GPA and involvement
of multiple systems. Therefore, the question of the disease activity and surgery
remains unanswered because all included patients undergoing surgery were in
remission with minimal or no local disease at the time of reconstruction.

The potential impact of immune-modulating medications (e.g., prednisone,

methotrexate, and cyclophosphamide) on increased complication rates such as
wound healing or wound infection is as yet unknown. Three of 40 GPA patients
(7.5%) developed a postoperative wound infection (23, 25) which was successfully
treated with antibiotics. In some studies antibiotics were administered
prophylactically which may reduce the rate of postoperative wound infections (26).
The acceptable dose for daily cortisone application without causing adverse effects
is unknown. Qian et al. (26) have an institutional protocol of maximum 10 mg
Prednisolone daily. Further investigations are required.

Four out of ten studies described the subjective improvement in nasal breathing
beside the improved aesthetic outcome (18, 20, 23, 24). Objective criteria of the
nasal airway or condition of the nasal mucosa before and/or after surgery were not
documented.

Implications for clinical practice

The authors experience from a series of reconstructive rhinoplasties in patients with
GPA is that the nasal septal cartilage and mucosa should not be opened, touched or
reconstructed during the surgery. Since GPA comes with remissions and

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 exacerbations, a reconstruction of the nose by rebuilding the nasal septum carries
the risk of recurrence of the saddle deformity. Moreover, the nasal mucosa is of poor
quality, scarred with chronic inflammation, crusts and poor vascularization. Thus, the
Accepted Article
underlying septal cartilage receives insufficient nutrition and oxygenation eventually
leading to a loss of cartilage tissue. Over time this process will lead to septal
perforations and loss of the cartilaginous dorsal support, retraction of the columella
and loss of tip support. It may also explain why there are a so few reports on
successful reconstruction of the septum, probably it just doesn't work. Typically, the
bony dorsum and bony part of the septum, lower lateral cartilages and upper lateral
cartilages are preserved in GPA. Therefore, instead of rebuilding the cartilaginous
septum, the authors favour to create a "self supporting" bony- or cartilaginous
structure that provides sufficient support to the mid-nasal-third and prevents
retraction of the columella. This structure is placed under the soft tissue envelope on
top of the bony pyramid and the anterior nasal spine. A single implant in a L-shaped
fashion or a strong costal columellar strut graft articulating with a costal dorsal onlay
graft can be used. According to our observation, the structure is located in an area
where tissues are preserved well, like the lower and upper lateral cartilages and
bony dorsum, far away from the diseased nasal cavity. Since the graft does not
depend on the vascularisation of the septal mucosa, the chance of resorption is
probably smaller.

Quality of evidence

The limitation of this study is that all included studies contained only a very limited
number of patients. 90% of the surgically treated patients were female. Therefore, no
general guidelines can be made at this time and the results are particularly
unrepresentative for male GPA patients. In addition, the mean follow-up was 2.6
years, therefore, long-term complications of surgical therapy cannot be commented
on. Furthermore, publication bias is possible since it is unclear if failed cases were
included in the reports.

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 Implications for research

In the future, larger cohorts of GPA should be monitored or even a registry including
a database of treatment and complications should be established to provide more
Accepted Article
rational recommendations for the optimal surgery time and the best graft. It would
also be of interest to know if patients benefit from antibiotics and immune-modulating
drugs in the pre- and postoperative phase. Detailed documentation of the
intraoperative status of the cartilaginous nasal framework and soft-tissues should
provide information if reconstructive measures should be taken beyond the nasal
dorsum. With contracture of the nasal lining, the upper lateral cartilages may also be
deformed and need to be reconstructed.

In conclusion, saddle nose reconstruction is a safe procedure in GPA patients in

remission with minimal local disease even if an increased rate of revision surgery
has to be expected compared with a typical collective of septorhinoplasty patients.
Further research regarding antibiotic prophylaxis, acceptable cortisone application,
functional outcomes measured with subjective and objective parameters and long-
term outcomes are required.

Conflict of interest disclosures and funding source: The authors report no

conflicts of interest relevant to this article and no financial support or funding.

Funding: No funding was received for this study.

Conflict of Interest: The authors have no conflict of interest to declare.
Ethical approval: This article does not contain any studies with human participants
performed by any of the authors.

This article is protected by copyright. All rights reserved.

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ccepted Articl
Table 1: Main characteristics of the eligible studies describing efficacy and safety of surgical reconstruction of external nasal deformities
in patients with granulomatosis with polyangiitis

Author Study Follow country No. of Patient Deformity No. Of Grafts/ flaps Upper No. of Compli- Success rate Disease
time up patients age surgeries; airway: revisions cations for graft relapse
(years) (female: (years) surgical systemic types
male) treatment involvemen
t
Noguchi 1991 3 Japan 1 (1:0) 38 1 saddle 1 dorsal Costal - Augmentat no 100% 0
et al. nose augmentation cartilage and ion of the
1991 17 and septal + nasal lining bilateral anterior
perforation repairment nasolabial nasal
flaps spine
Pirsig et 1990 2 DE 1 (1:0) 46 1 saddle 1 dorsal Conchal - None no 100% 1
al. 1993 18 nose and augmentation cartilage
septal
perforation
Duffy et 1998 2 USA 1 (0:1) 45 1 saddle 1 dorsal Costal - None no 100% 0
al. 1998 19 nose and augmentation cartilage and
septal + nasal lining bilateral facial
perforation repairment artery
musculomuco
sal flaps
Nishiike 1998- 3 Japan 1/5* (1:0) 22 1 saddle 1 dorsal iliac crest 5:0 none no 100% 1
et al. 2003 nose augmentation
2004 20 repair
Shipchan 2002- 2 (1-3) USA 4/15* - 4 saddle 4 dorsal calvarial bone - none no 100% 0
dler et al. 2007 nose and augmentation
2008 21 septal repairs
perforation
Congdon 1976- 5 (1-15) USA 13 43 (24- 12 saddle 16; Costal 8:5 3 dorsal 1 graft Costal cartilage 0
et al. 2000 (12:1) 73) nose 12 dorsal cartilage (6/15, augmentat infection, (83%), calvarial
2002 22 1 alar rim augmentation 40%), calvarial ion repairs 3 late bone (75%),
repairs bone (4/15, graft composite auricular
1 alar rim 27%), resortpti (100%), iliac bone
repair irradiated rib on (100%), conchial
(1/15, 7%), cartilage (100%),
irradiated dura septal bone (100%),
(1/15, 7%), irradiated rib and
cochal dura (0%)
cartilage (1/15,
7%), iliac crest
(1/15, 7%),
bony septum
(1/15, 7%),
auricular graft
for alar rim

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ccepted Articl repair

Vogt et al. 2001- 3,5 (1,5- DE 4 (4:0) 33 (26- 4 saddle- 4 dorsal Costal - None no 100% 0
2010 23 2006 5) 42) nose augmentation cartilage
repair
Sepehr et 2005- 1,5 (1- Canada 10 (10:0) 36 (21- 10 saddle- 12; Costal 8:2 2 2 graft primary success 1
al. 2011 24 2009 2,5) 49) nose 10 dorsal cartilage dorsal infection, 80%, overall
augmentation augmentat 1 graft success 100%
repair ion repairs resorptio
n, 1
columell
ar
necrosis
Qian et al. 2008- 3 (1,5-5) Australia 4/5* (3:1) 40 (25- 4 4 dorsal Costal - 1 no 100% 1
2014 25 2011 74) saddle-nose augmentation cartilage revision
repair for
asymmetr
y of
nostrils
Bennett et 2010 1 UK 1 (1:0) 22 1 saddle Augmentation filler Restylane - - 0 100% -
al. 2010 26 nose ®
Sachse et 2010 - DE 1 - 1 septal 1 septal Costal - None No 100% -
al. 13 perforation perforation cartilage and
repairment bilateral f
turbinate
pedicled
mucosal flaps

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Accepted Article

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